GE Violated Danish Drug Reporting Law in Omniscan Case

Danish drug regulators concluded in a ruling last month that GE's health care unit failed to promptly and completely inform regulators about a patient who died after experiencing adverse effects from the company's MRI drug Omniscan. Though that's a violation of Danish law, the regulators said the statute of limitations had expired and they wold pursue no further action.

General Electric's health care unit failed to promptly and completely inform regulators about a patient who died after experiencing adverse effects from the company's MRI drug Omniscan, Danish drug regulators concluded in a ruling last month.

The finding by the Danish Medicines Agency comes in the case of a Danish woman who had been injected with Omniscan for a magnetic resonance scan in 2002 and gradually became immobilized and died of a lung embolism the following year.

The woman, Birthe Madsen, is believed to be among the first patients whose use of Omniscan and similar medical imaging drugs was associated with a rare and potentially crippling disease now known as nephrogenic systemic fibrosis, or NSF. Hundreds of patients became ill after Madsen's death, before regulators and drug companies learned enough about the risks to begin issuing alerting doctors a few years later.

Reviewing the reasons Madsen died, a Danish government insurance agency determined in 2004 that Omniscan caused her immobility and in turn her death. Although this was relayed to GE Healthcare, the company did not immediately report it to the medicines agency as required, nor did a follow-up include the insurance agency's conclusion that Madsen's death could be attributed to the drug.

Although the reporting lapses violated Danish drug law, the medicines agency told GE Healthcare in a May 21 letter that the statute of limitations had expired and that it would not pursue further action against the company.

GE Healthcare maintains that its reporting about Omniscan's side effects has been proper, and spokesman Jeff DeMarrais said in an e-mail that the woman's death was not initially attributed to Omniscan because the fatal embolism occurred during a lengthy course of treatment "following the patient's adverse reaction."

The ruling by the Danish Medicine Agency, coming years after the reporting lapse, appears to have been prompted by an inquiry last October from a member of the Danish parliament about the agency's response after cases of NSF first came to light in early 2006.

GE currently is contesting more than 400 lawsuits involving U.S. patients who say they contracted NSF after being injected with Omniscan. The company says it acted properly to protect patients and denies its drug causes NSF. Some manufacturers of competing products also have been sued, but in far fewer numbers than GE.

One of the major points of debate in the litigation concerns what GE Healthcare knew and disclosed to regulators about Omniscan's risks. The company contends it has been proactive and cooperative, while the plaintiffs claim the company failed to disclose damaging information about the drug and put patients in jeopardy.

Critics of GE Healthcare say more forthright disclosure might have helped doctors and regulators respond earlier and more effectively. Among them is Madsen's son, Casper Schmidt, a Copenhagen lawyer who has carefully documented her case and the actions of various Danish authorities.

"If my mother's case had been reported more accurately, and if the company had to explain why a patient died," Schmidt said in an e-mail, "it would have helped enable doctors and regulators to better understand the disease earlier."

Drug manufacturers in the United States and Europe are required to promptly report serious adverse reactions so that regulators and medical providers can monitor a product's safety. They also must update the reports as new information about a case develops. In the U.S., the Food and Drug Administration logs the reports in a database.

At the time Madsen was exposed to Omniscan in 2004, tens of millions of patients who had undergone MRIs had been safely injected with such products, known as contrast agents, to enhance the images.

Omniscan, approved for use in the United States in 1993, is among a class of such agents that rely on gadolinium, a highly toxic metal. The body normally eliminates the drug quickly after treatment, except in some patients who have impaired kidney function.

Madsen was such a patient. According to Schmidt's timeline of her treatment, she had at least one dialysis treatment before being injected with Omniscan in January 2002 to evaluate whether her veins were healthy enough for a kidney transplant. She experienced a cascade of crippling symptoms until her death in October 2003 at age 55.

Madsen's adverse reactions prompted a medical review by a Danish government insurance agency, called Patientforsikringen, or Patient Insurance Agency, to see whether she had suffered drug side effects that might qualify her for state compensation.

The review determined that while Madsen died of a pulmonary embolism, her "immobilization was caused by the acknowledged pharmaceutical injury."

That conclusion was reported to GE Healthcare on June 1, 2004, but the company failed to relay the information as required, the Danish Medicines Agency said in its May letter. In addition, the agency said a follow-up report from GE Healthcare, while noting several of Madsen's adverse reactions, was insufficient because it did not repeat the state insurance agency's finding that she died from an embolism due to being immobilized.

DeMarrais, the GE spokesman, said that at the time, the company's drug safety experts had a different understanding of Madsen's death.

"Our filings regarding the case in question reflect that, as of 2004," DeMarrais wrote, the drug safety unit "had not concluded, based on the information available at the time and in good faith, that the patient's death had been caused by the adverse event that had been linked to the administration of Omniscan, but rather by a pulmonary embolism occurring during a protracted medical course following the patient's adverse reaction."

In its May letter, the Danish Medicines Agency said it had combed its files and could find no report from GE about Madsen in June 2004. DeMarrais, however, said the company believes a report was sent that month "at the same time as it was sent to other regulators, as confirmed by the FDA's receipt of this filing."

At ProPublica's request, Conor McKechnie, another company spokesman, provided a copy of the FDA filing with Madsen's name and some other information redacted. (The filing was on the letterhead of Amersham Health, the British maker of scanning drugs that GE acquired in late 2003 and early 2004.)

The filing references "new information" from the Danish insurance agency and states that the patient involved "suffered pulmonary embolism due to immobilization and died." But it does not quote the insurance agency's conclusion that "pharmaceutical injury" was to blame for Madsen's immobility.

McKechnie said the FDA filing is accurate and mentioned immobilization, the embolism and death. DeMarrais said GE Healthcare also has submitted half a dozen more supplemental filings on the case over the last six years. "It would be a mistake," he added, "to attach unwarranted significance to this particular case at this juncture."

"It is our position that, consistent with the relevant health risk communication protocols, we provided complete and timely reports to the DMA and other global authorities regarding the adverse events associated with Omniscan that were reported to us," DeMarrais said in his e-mail.

Dr. Sidney Wolfe, director of the health research group at the consumer watchdog organization Public Citizen, said GE should have been more forthcoming in 2004.

"Incomplete and misleading reports such as this undermine the ability of the government to make decisions more quickly to improve the public health," said Wolfe, who is on an FDA advisory committee that late last year reviewed Omniscan and other contrast agents.

In May 2006, following the disclosure of 20 NSF cases in Copenhagen, GE Healthcare issued a safety alert to the DMA and regulators around the world. It discussed the new cases and attached a brief description of each one. In the section involving Madsen, the company reported her death as "unrelated to Omniscan."

By 2007, at the urging of regulators, the manufacturers of gadolinium-based agents put warnings about NSF on their labels. Three years later, much about the disease remains a mystery, including the exact cause. Patients experience a painful hardening or thickening of skin around the joints. The disease can be disfiguring and may attack internal organs.

As of last fall, the Patientforsikringen had reviewed 38 cases in which people exposed to Omniscan had suffered injury or death. In 26 cases, the insurance agency determined that GE Healthcare's drug was the likely cause, according to a spokesman. In those cases, including Madsen's, the agency made payments to the victims or their relatives.

GE Healthcare has the opportunity to appeal the insurance agency's decisions but has not done so, the Patientforsikringen spokesman said in an e-mail last fall. McKechnie said the company did not appeal because it was not a direct party to the agency's decision.

DeMarrais said the company would respond to the Danish Medicines Agency's finding of a reporting violation, which can be appealed.

Madsen's name is redacted in the May 21 letter from the agency, but it was confirmed by her son and by matching the details in the letter with other public information.

Nephrogenic Systemic Fibrosis (NSF) is a potentially fatal disease that is characterized by painful swelling and thickening of the skin. There is no known cure or definitive cause for NSF, though it appears to affect only MRI patients who have kidney problems.

Contrast Agents

Contrast agents are drugs administered by radiologists to improve the visibility of a patient’s internal body structure. Omniscan is one of General Electric’s contrast agents.

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